1. Field of the Invention
The present invention relates to the preparation of topotecan or pharmaceutically acceptable salt thereof from 10-hydroxycamptothecin.
2. Description of the Related Art
U.S. Pat. No. 5,004,758 discloses topotecan, (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,14(4H,12H)dione monohydrochloride (also known as 9-dimethylaminomethyl-10-hydroxycamptothecin, etc.). It has the following structural formula:

Topotecan hydrochloride for injection is marketed in the U.S. as a cancer chemotherapeutic agent, having the trade name HYCAMTIN®.
The conventional process for making topotecan is by a Mannich reaction of 10-hydroxy-camptothecin. For example, U.S. Pat. No. 5,734,056 discloses the reaction of bis(dimethylamino)methane; bis(N-morpholino)methane; bis(N-methylpiperazinyl)methane; bis(4′-piperidinopiperidinyl)methane; bis(cyclopropylamino)methane; bis(N-methylanilino)methane; or bis(cyclohexylamino)methane with 10-hydroxy-camptothecin to produce 9-substituted camptothecins, which include topotecan.
There is still a need to develop a simple, commercially feasible process of making topotecan or pharmaceutically acceptable salt thereof that has fewer impurities present.